Clinical implications of C6 complement component deficiency.

Background: Terminal complement component deficiencies are risk factors for neisserial infections. Objective: To review the clinical characteristics, the diagnosis and the management of patients with a terminal complement component deficiency. Methods: Pertinent articles were selected and reviewed in relation to a case presentation of C6 deficiency. Results: A case of a 56-year old patient with a history of meningitis, chronic rash, and C6 deficiency was presented, followed by discussion of clinical characteristics, diagnosis, and management of terminal complement component deficiencies. Clinical pearls and pitfalls were reviewed for the practicing allergist/immunologist and fellow-in-training. Conclusion: C6 deficiency is the most common terminal complement component deficiency and can present later in age with N. meningitidis infections. Patients can be screened for terminal complement component deficiency by checking CH50.

Risk factors for acquisition of meningococcal carriage in the African meningitis belt.

OBJECTIVE: To investigate potential risk factors for acquisition in seven countries of the meningitis belt. METHODS: Households were followed up every 2 weeks for 2 months, then monthly for a further 4 months. Pharyngeal swabs were collected from all available household members at each visit and questionnaires completed. Risks of acquisition over the whole study period and for each visit were analysed by a series of logistic regressions. RESULTS: Over the course of the study, acquisition was higher in: (i) 5-to 14-year olds, as compared with those 30 years or older (OR 3.6, 95% CI 1.4-9.9); (ii) smokers (OR 3.6, 95% CI 0.98-13); and (iii) those exposed to wood smoke at home (OR 2.6 95% CI 1.3-5.6). The risk of acquisition from one visit to the next was higher in those reporting a sore throat during the dry season (OR 3.7, 95% CI 2.0-6.7) and lower in those reporting antibiotic use (OR 0.17, 95% CI 0.03-0.56). CONCLUSIONS: Acquisition of meningococcal carriage peaked in school age children. Recent symptoms of sore throat during the dry season, but not during the rainy season, were associated with a higher risk of acquisition. Upper respiratory tract infections may be an important driver of epidemics in the meningitis belt.

OBJECTIF: Investiguer les facteurs de risque potentiels d'acquisition dans sept pays de la ceinture de la méningite. MÉTHODES: Des ménages ont été suivis toutes les deux semaines pendant deux mois, puis tous les mois pendant quatre mois. Des prélèvements pharyngés sur écouvillons ont été collectés auprès de tous les membres disponibles du ménage à chaque visite et des questionnaires ont été remplis. Les risques d'acquisition sur l'ensemble de la période d'étude et pour chaque visite ont été analysés par une série de régressions logistiques. RÉSULTATS: Au cours de l'étude, l'acquisition a été plus élevée chez: (i) les 5-14 ans, par rapport à ceux âgés de 30 ans ou plus (OR = 3,6; IC95%: 1,4-9,9); (ii) les fumeurs (OR = 3,6; IC95%: 0,98-13); et (iii) les personnes exposées à la fumée de bois à la maison (OR = 2,6; IC95%: 1,3-5,6). Le risque d'acquisition d'une visite à l'autre était plus élevé chez les personnes signalant un mal de gorge pendant la saison sèche (OR = 3,7; IC95%: 2,0-6,7) et plus faible chez celles signalant une utilisation d'antibiotique (OR = 0,17; IC95%: 0,03-0,56). CONCLUSIONS: L'acquisition du portage du méningocoque a culminé chez les enfants d'âge scolaire. Les symptômes récents de maux de gorge pendant la saison sèche, mais pas pendant la saison des pluies, étaient associés à un risque d'acquisition plus élevé. Les infections des voies respiratoires supérieures pourraient être un facteur important d'épidémies dans la ceinture de la méningite.

Atmospheric Dust, Early Cases, and Localized Meningitis Epidemics in the African Meningitis Belt: An Analysis Using High Spatial Resolution Data.

BACKGROUND: Bacterial meningitis causes a high burden of disease in the African meningitis belt, with regular seasonal hyperendemicity and sporadic short, but intense, localized epidemics during the late dry season occurring at a small spatial scale [i.e., below the district level, in individual health centers (HCs)]. In addition, epidemic waves with larger geographic extent occur every 7-10 y. Although atmospheric dust load is thought to be an essential factor for hyperendemicity, its role for localized epidemics remains hypothetic. OBJECTIVES: Our goal was to evaluate the association of localized meningitis epidemics in HC catchment areas with the dust load and the occurrence of cases in the same population early in the dry season. METHODS: We compiled weekly reported cases of suspected bacterial meningitis at the HC resolution for 14 districts of Burkina Faso for the period 2004-2014. Using logistic regression, we evaluated the association of epidemic HC-weeks with atmospheric dust [approximated by the aerosol optical thickness (AOT) satellite product] and with the observation of early meningitis cases during October-December. RESULTS: Although AOT was strongly associated with epidemic HC-weeks in crude analyses across all HC-weeks during the meningitis season [odds ratio (OR) [Formula: see text]; 95% CI: 4.90, 9.50], the association was no longer apparent when controlling for calendar week (OR [Formula: see text]; 95% CI: 0.60, 1.50). The number of early meningitis cases reported during October-December was associated with epidemic HC-weeks in the same HC catchment area during January-May of the following year (OR for each additional early case [Formula: see text]; 95% CI: 1.06, 1.21). CONCLUSIONS: Spatial variations of atmospheric dust load do not seem to be a factor in the occurrence of localized meningitis epidemics, and the factor triggering them remains to be identified. The pathophysiological mechanism linking early cases to localized epidemics is not understood, but their occurrence and number of early cases could be an indicator for epidemic risk. https://doi.org/10.1289/EHP2752.

Short-term changes in the health state of children with group B meningococcal disease: A prospective, national cohort study.

OBJECTIVES: The short-term impact of childhood invasive meningococcal disease (IMD) on quality-of-life (QoL) remains largely unquantified. This study aimed to quantify QoL loss at the point when illness was at its worst, and assess health state recovery in the months following illness. METHODS: Parents of children aged <16 years with laboratory-confirmed meningococcal group B (MenB) disease in England, with onset dates from November 2012 to May 2013 were asked to complete a short questionnaire, which included EQ-5DY, a version of EQ-5D for 8-15 year-olds. The parents, or child if able, were asked to complete the questionnaires while considering the child's health on the worst day of illness and on the date the questionnaires were completed. RESULTS: The overall response rate was 43% (109/254 children), with no significant differences between respondents and non-respondents. The median time from disease onset to questionnaire completion was 134 days (interquartile range (IQR), 92 to 156 days). After imputation, the median health index was -0.056 (IQR, -0.073 to 0.102) on the worst day of illness, and 1 (IQR 0.866 to 1.000) on the date of questionnaire completion. The respective Visual Analogue Scores (VAS) were 6.5/100.0 (IQR, 0.0 to 20.0) and 95.0/100.0 (IQR, 90.0 to 100.0). The health state of cases with long-term sequelae (n = 41) was significantly worse at follow-up than those who recovered uneventfully (n = 64; 90.0 vs. 98.0; p<0.001), although there was no significant difference on the worst day of illness (5.0 vs. 10.0; p = 0.671). CONCLUSIONS: This work has provided, for the first time, a quantitative estimate of QoL loss at the peak of illness and in the months after MenB disease in children. The magnitude of QoL loss is staggering, with the reported health state being at, or close to, the worst possible outcome imaginable. This study highlights the difficulties in measuring the impact of illness in young children, who often have the highest burden of potentially preventable infectious diseases.

Preventative Care in the Patient with Inflammatory Bowel Disease: What Is New?

Patients with inflammatory bowel disease (IBD) do not receive routine preventative care at the same rate as general medical patients. This patient population is at increased risk of vaccine preventable illness such as influenza and pneumococcal pneumonia. This review will discuss health maintenance needs and preventative care issues in patients with IBD.

Imported and Indigenous cases of Invasive Meningocococcal Disease W:P1.5,2:F1-1: ST-11 in migrants' reception centers. Italy, June-November 2014.

We report about three unliked cases of meningococcal meningitis caused by the ST-11/ET-37 strain of Neisseria meningitidis serogroup W. Two of the three cases, detected in Sicily on June and July 2014, were migrants from Mali and Eritrea. The third case was a fatal meningitis occurred on November 2014 in a 37 years old man, working in an immigrant center in Calabria. This report suggests that tetravalent conjugate vaccines (ACYW) should be actively offered to the staff of migrants' reception centers.

Serogroup W Meningitis Outbreak at the Subdistrict Level, Burkina Faso, 2012.

In 2012, Neisseria meningitidis serogroup W caused a widespread meningitis epidemic in Burkina Faso. We describe the dynamic of the epidemic at the subdistrict level. Disease detection at this scale allows for a timelier response, which is critical in the new epidemiologic landscape created in Africa by the N. meningitidis A conjugate vaccine.

Costs of surviving meningococcal disease in Spain: evaluation for two cases of severe meningitis and septicaemia.

OBJECTIVES: The aim of this study was to count the lifelong rehabilitation costs associated with surviving meningococcal disease with major sequelae from the perspective of the Spanish National Healthcare System (NHS) and the national government. METHODS: Two severe scenarios describing meningococcal disease were developed, one case that represented meningococcal septicaemia and another case for meningococcal meningitis. The scenarios were developed based on a literature review on severe sequelae of meningococcal disease, and discussions with paediatricians who have been responsible for the treatment of children with this disease in Spain. Second, a detailed list of all health, educational and social care resources used by survivors during their acute illness and during the rest of their lives and by family members was obtained by interviewing survivors and their families. Professionals in health and social care were also interviewed to complete the list of resources and ensure the scenario's were accurate. The costs attributed to these resources were obtained from tariff lists, catalogues and published information by the national authorities. All costs were based on a life expectancy of a survivor of 70 years and expressed in EUR 2012. RESULTS: In this study it was estimated that the lifelong discounted rehabilitation costs associated with the treatment of long-term sequelae due to meningococcal disease are approximately €1180,000-€1400,000. Medical care and social care were the main cost drivers for both septicaemia and meningitis. Annual costs showed to be the largest in the first year after diagnosis of the disease for both cases, due to high hospital admission and medical care costs during this period and decreased significantly over the years. CONCLUSION: This study shows that the lifelong rehabilitation costs associated with the survival of meningococcal disease with severe sequelae place an important burden on the NHS budget and governmental resources in Spain.

Maternal and perinatal factors associated with subsequent meningococcal, Haemophilus or enteroviral meningitis in children: database study.

We used a database of 248 659 births, with follow-up to subsequent disease, in the Oxford record linkage archive (1979-1999) to study the influence of family, maternal, and perinatal factors on subsequent hospital admission for meningococcal, Haemophilus, and enteroviral meningitis in the children. In this summary, we report key findings that were significant in multivariate analysis. Meningococcal meningitis was significantly associated with maternal smoking [odds ratio (OR) 2·1, 95% confidence interval (CI) 1·2-3·7]. Haemophilus meningitis was associated with having older siblings (e.g. second child compared to first-born, OR 3·3, 95% CI 2·0-5·6). Enteroviral meningitis was associated with low birth weight (OR 2·2, 95% CI 1·3-3·6) and male sex (OR 1·7, 95% CI 1·2-2·3). The mothers of six of the 312 children with enteroviral meningitis had previously had enteroviral meningitis themselves. We concluded that several maternal characteristics influence the risk of these types of meningitis.

Autoantibody stabilization of the classical pathway C3 convertase leading to C3 deficiency and Neisserial sepsis: C4 nephritic factor revisited.

C3 deficiency is a rare disorder that leads to recurrent pyogenic infections. Here we describe a previously healthy 18 y/o Caucasian male with severe meningococcal disease. Total hemolytic activity was zero secondary to an undetectable C3. The C3 gene was normal by sequencing. Mixing the patient's serum with normal human serum led to C3 consumption. An IgG autoantibody in the patient's serum was identified that stabilized the classical pathway C3 and C5 convertases, thus preventing decay of these enzyme complexes. This autoantibody is an example of a C4 nephritic factor, with an additional feature of stabilizing the C5 convertase. Previous patients with C4 nephritic factor had membranoproliferative glomerulonephritis. Two years after presentation, this patient's C3 remains undetectable with no evidence of renal disease. We revisit the role of autoantibodies to classical pathway convertases in disease, review the literature on C4-NeF and comment on its detection in the clinical laboratory.

Outcomes of invasive meningococcal serogroup B disease in children and adolescents (MOSAIC): a case-control study.

BACKGROUND: Serogroup B meningococcal disease is the commonest cause of meningitis and septicaemia in high-income countries. Assessment of new serogroup B meningococcal vaccines is hampered by a scarcity of data on the burden of disease in survivors. We aimed to estimate the disease burden in children having survived serogroup B meningococcal disease. METHODS: In this case-control study, we recruited children from the UK National Meningococcal Registry between May, 2008, and September, 2010. Eligible children were survivors who had had serogroup B meningococcal disease confirmed by culture or PCR and were aged 1 month to 13 years at disease. Age-matched and sex-matched controls were recruited through the family doctor of the children who had the meningococcal disease. Physical, psychological, neurocognitive, and educational outcomes were assessed through a standardised interview with validated instruments. We did matched analyses using generalised estimating equations (GEE). Researchers were masked to the children's serogroup B meningococcal status. FINDINGS: Of the 537 children who had serogroup B meningococcal disease and were available for recruitment, 245 were assessed. 328 controls were also recruited; 221 controls were matched with a case and 107 were additional unmatched controls. The mean age was 6·5 (SD 2·8) years in children with serogroup B meningococcal disease and 6·9 (2·9) in controls. In the full sample, children who had serogroup B meningococcal disease were more likely than controls to have bilateral sensorineural hearing loss of 40 dB or more (unmatched 11 [5%] of 232 children with meningococcal disease vs three [<1%] of 318 controls; matched odds ratio [OR] 4·8, 95% CI 1·3 to 17·4, p=0·02), lower full-scale IQ (matched mean 99·5 for children with meningococcal disease and 107·2 for controls; matched coefficient -7·6, 95% CI -9·9 to -5·4, p<0·0001), and psychological disorders (61 [26%] of 235 children with meningococcal disease vs 33 (10%) of 322 controls; matched full sample OR 2·6, 1·6 to 4·2, p<0·0001). Disabling amputations were noted in three (1%) of 239 children who had serogroup B meningococcal disease compared with none of the 322 controls. Children with meningococcal disease were also more likely to have deficits in executive function and multiple aspects of memory. Deficits were identified in 87 (36%) of 244 children with serogroup B meningococcal disease and 49 (15%) of 328 controls (matched OR 2·7, 1·8 to 4·1, p<0·0001). Major disabling deficits were identified in 21 (9%) of 244 children with meningococcal disease compared with six (2%) of 328 controls (matched OR 5·0, 2·0 to 12·6, p=0·001). No significant differences were noted in attentional function or post-traumatic stress disorder between children with serogroup B meningococcal disease and controls. INTERPRETATION: Most children survive serogroup B meningococcal disease without major sequelae. However, about a tenth have major disabling deficits and more than a third have one or more deficits in physical, cognitive, and psychological functioning, with the additional burden of memory deficits and executive function problems. These findings should help to guide assessments of new vaccines and suggest that all survivors of serogroup B meningococcal disease should be screened for psychological disorders and cognitive deficits in addition to hearing loss. FUNDING: Meningitis Trust and Big Lottery Fund, UK.

Complete deficiency of the sixth complement component (C6Q0), susceptibility to Neisseria meningitidis infections and analysis of the frequencies of C6Q0 gene defects in South Africans.

Complete complement component 6 deficiency (C6Q0) is a co-dominant genetic disease presenting as increased susceptibility to invasive Neisseria meningitidis infections. Affected individuals have two affected alleles which can be homozygous or compound heterozygous for the particular gene defects they carry. This disorder has been diagnosed relatively frequently in Western Cape South Africans. Affected patients are prescribed penicillin prophylaxis. In 2004 we commenced a clinical follow-up study of 46 patients. Of these, 43 had family age-matched C6 sufficient controls. Participants were classified as either (i) well, or (ii) having a serious illness (SI) or died (D). An SI was a long-term illness that did not allow the performance of normal daily activities. Among 43 patients, 21 were well and 22 were SI/D, while among 43 matched controls, 35 were well and eight were SI/D. This difference is highly significant. Among all 46 C6Q0 patients, those who had had recurrent infection had significantly more SI/D than those who had suffered none or one infection. Thus, this work demonstrates the long-term serious outcome of repeated meningococcal disease (MD) episodes. We investigated the frequencies of four C6Q0 pathogenic mutations known to affect Cape patients (828delG, 1138delC, 821delA and 1879delG) in 2250 newborns. A total of 103 defective alleles (2·28%) and three affected C6Q0 individuals were detected. For all defects combined, 5·24 affected subjects (C6Q0) are expected among 10,000 individuals. What is still unknown is the number of C6Q0 individuals who suffer MD or other infectious diseases.

Desenvolvimento e manutenção de memória imunológica após imunização contra Neisseria meningitidis B com a vacina VA-MENGOC-BC / Development and maintenance of immunological memory after immunization against Neisseria meningitidis B with vaccine VA-MENGOC-BC

Neisseria meningitidis é uma das principais causas de meningite bacteriana e septicemia em todo o mundo, acometendo principalmente crianças menores de 4 anos. Atualmente, não existe uma vacina universal contra o meningococo B (MenB). A imunidade protetora contra o meningococo caracteriza-se pela presença e persistência de anticorpos bactericidas, porém pouco se sabe sobre os mecanismos de desenvolvimento desta memória sorológica. Avaliamos em modelo animal e em humanos, a geração e manutenção das células secretoras de anticorpos (ASC) e dos linfócitos B de memória (LBm) após vacinação contra MenB. Utilizamos como referência a vacina diftérica (dt ou DTP), considerada ter ótima eficácia em humanos. Para o estudo em modelo animal, grupos de 6 a 8 camundongos suíços, fêmeas, de 5 a 6 semanas, foram imunizados com 3 doses da vacina VA-MENGOC-BC ou DTP, via intramuscular, com intervalo de 2 semanas entre as doses. Aproximadamente 2, 4 ou 6 meses após a última dose, os animais receberam a dose reforço. A vacina anti-MenB induziu uma resposta primária de ASC maior que a resposta à dose reforço. Ao contrário, a resposta de ASC à vacina dT foi maior após o booster. A resposta de LBm anti-MenB permaneceu constante (média de 1%) ao longo de todo o estudo, mas a resposta ao toxóide diftérico (TD) foi maior após o booster (média de 1,9%) que após a imunização primária. A concentração de IgC, anticorpos bactericidas e opsonizantes contra MenB foi dose-dependente e foi reativada após a administração das doses reforços. Esses resultados sugerem que os LBm presentes no baço foram responsáveis pela forte resposta de anticorpos observada após a dose reforço. Para o TD, ambas ASC e LBm foram importantes na manutenção da memória sorológica. Para o estudo em humanos, seis voluntários foram imunizados com 3 doses da vacina VA-MENGOC-BC, via intramuscular, com intervalo de 6 a 7 semanas entre as doses. Seis meses após a imunização primária, os indivíduos receberam uma dose...

Neisseria meningitides is one of the leading causes of bacterial meningitis and septicemia worldwide, particularly in children less than four years old. Currently, there is no universal vaccine agoinst serogroup B meningococcus (MenB). Protective immunity against meningococcus is characterized by the presence and persistence of bactericidal antibody, but little is known about the mechanisms of development of the serological memory. In this study, we evaluated in animal model and in humans the generation and maintenance of antibody secreting cells (ASC) and memory B cell after vaccination against MenB. We used the diphtheria vaccine (dT or DTP) as a reference for efficacy in humans. Five to six-week old female Swiss mice in groups of 6 to 8 were immunized with three intramuscular injections of VA-MENGOC-BC or DTP vaccine 2 weeks apart. Approximately 2, 4 or 6 months after the last dose, mice received a booster injection of the vaccine. Vaccination against MenB induced a higher ASC primary response compared with the booster response. In contrast, ASC response to dT was higher after booster than after primary immuinization. Memory B-cell to MenB remained at constant levels (mean of 1%) during the whole study, but the response to diphtheria toxoid (TD) was higher after boosting (mean of 1.9%) when compared with the primary response. IgG, bactericidal and opsonic antibody concentrations to MenB was dose-dependent and was reactivated after booster doses. These data suggest that spleen memory B-cells were responsible for the strong boosting antibody response to MenB. For TD, both ASC and memory B-cell were important for maintenance of the serological memory. For the human study, six volunteers were immunized with three intramuscular injections of VA-MENGOC-BC 6 to 8 weeks apart. Six months after the last dose, subjects received a booster dose. Another group of volunteers (n=5) were immunized with a booster dose of dT vaccine. Three doses of vaccine...

[Safety and efficacy of vaccination in children after stem cell transplantation. Part 1]. / Bezpieczenstwo i skutecznosc szczepien ochronnych prowadzonych u dzieci po przeszczepieniu komórek krwiotwórczych. Doniesienie 1.

UNLABELLED: The aim of the study was the evaluation of safety and efficacy of vaccination in children after stem cell transplantation. PATIENTS AND METHODS: 21 patients, 1.4-22 (average 7.8) years old, 13 boys and 8 girls after autologous (11-52%) and allogeneic (10-48%) transplantation were included in the vaccination protocol. Indications for transplantation were: neoplastic disease--16, immunodeficiencies--3 and aplastic anaemia 2 cases. Time between transplantation and beginning of vaccination protocol was 0.8-4 (average 1.5) years. Vaccination protocol was constructed on the basis of the European Group for Blood and Marrow Transplantation indications. We have evaluated: (1) quality of recipient immune reconstitution and protection against common pathogens (2) immunogenicity of revaccination schedule; (3) safety of the vaccination programme. RESULTS: With the exception of one patient presenting with repeated fever, lymph node enlargement, muscle and joint pain, no important side effects were observed. Meningococcial meningitis developed in one patient who refused vaccination. The mean concentrations of antibodies in the plasma before and after vaccination were as follows: anti-diphteria (54; 2285), anti-tetanus (136; 3149) and anti-hepatitis B virus (anti-HBs: 24; 474) IU/ml. CONCLUSIONS: (1) Vaccination in patients after transplantation is efficient and well tolerated. (2) Significant increase of antibody level was detected. (3) Any delay in beginning the vaccination can result in life threatening complications.

The meningococcal ABC-Type L-glutamate transporter GltT is necessary for the development of experimental meningitis in mice.

Experimental animal models of bacterial meningitis are useful to study the host-pathogen interactions occurring at the cerebral level and to analyze the pathogenetic mechanisms behind this life-threatening disease. In this study, we have developed a mouse model of meningococcal meningitis based on the intracisternal inoculation of bacteria. Experiments were performed with mouse-passaged serogroup C Neisseria meningitidis. Survival and clinical parameters of infected mice and microbiological and histological analysis of the brain demonstrated the establishment of meningitis with features comparable to those of the disease in humans. When using low bacterial inocula, meningococcal replication in the brain was very efficient, with a 1,000-fold increase of viable counts in 18 h. Meningococci were also found in the blood, spleens, and livers of infected mice, and bacterial loads in different organs were dependent on the infectious dose. As glutamate uptake from the host has been implicated in meningococcal virulence, mice were infected intracisternally with an isogenic strain deficient in the ABC-type L-glutamate transporter GltT. Noticeably, the mutant was attenuated in virulence in mixed infections, indicating that wild-type bacteria outcompeted the GltT-deficient meningococci. The data show that the GltT transporter plays a role in meningitis and concomitant systemic infection, suggesting that meningococci may use L-glutamate as a nutrient source and as a precursor to synthesize the antioxidant glutathione.

Review of meningococcal infection in children at a United Kingdom hospital.

Sixty-nine children were identified and evaluable. Forty-one (60%) presented with hypotension and/or abnormal neurological signs. In 34 (49%) a petechial rash was present on admission. Of note, 13 (19%) had a non-petechial rash, and rash was absent in 19 (28%). Twenty-one (30%) presented with meningism or meningitis. In one child the illness was so mild that the child was discharged prior to making a diagnosis. Five children died (7%). Sixty-three cases (91%) were diagnosed by blood or cerebrospinal fluid culture; these investigations remain the mainstay of diagnosis.

Environmental exposures and invasive meningococcal disease: an evaluation of effects on varying time scales.

Invasive meningococcal disease (IMD) is an important cause of meningitis and bacteremia worldwide. Seasonal variation in IMD incidence has long been recognized, but mechanisms responsible for this phenomenon remain poorly understood. The authors sought to evaluate the effect of environmental factors on IMD risk in Philadelphia, Pennsylvania, a major urban center. Associations between monthly weather patterns and IMD incidence were evaluated using multivariable Poisson regression models controlling for seasonal oscillation. Short-term weather effects were identified using a case-crossover approach. Both study designs control for seasonal factors that might otherwise confound the relation between environment and IMD. Incidence displayed significant wintertime seasonality (for oscillation, P < 0.001), and Poisson regression identified elevated monthly risk with increasing relative humidity (per 1% increase, incidence rate ratio = 1.04, 95% confidence interval: 1.004, 1.08). Case-crossover methods identified an inverse relation between ultraviolet B radiation index 1-4 days prior to onset and disease risk (odds ratio = 0.54, 95% confidence interval: 0.34, 0.85). Extended periods of high humidity and acute changes in ambient ultraviolet B radiation predict IMD occurrence in Philadelphia. The latter effect may be due to decreased pathogen survival or virulence and may explain the wintertime seasonality of IMD in temperate regions of North America.